Methods of administering solriamfetol to lactating women

ABSTRACT

Provided herein according to some embodiments is a method for decreasing the potential for adverse events from solriamfetol in an infant fed breast milk obtained from a subject treated with solriamfetol comprising: orally administering the solriamfetol to the subject at a daily dose of about 37.5 mg to about 300 mg; and feeding the infant breast milk from the subject at least about 5 hours after administering the solriamfetol to the subject, thereby decreasing potential for adverse events from solriamfetol in an infant.

STATEMENT OF PRIORITY

This application is a continuation of and claims priority to U.S.application Ser. No. 18/148,682 filed Dec. 30, 2022.

FIELD OF THE INVENTION

The present invention relates to methods of administering solriamfetolto a lactating subject while reducing the potential for adverse eventsfrom solriamfetol in an infant fed breast milk from the subject.

BACKGROUND OF THE INVENTION

Solriamfetol is a selective dopamine and norepinephrine reuptakeinhibitor that has received marketing approval in the US for improvingwakefulness in adult subjects with excessive daytime sleepiness (EDS)associated with narcolepsy or obstructive sleep apnea (OSA).Solriamfetol has been demonstrated to be useful in the treatment of avariety of disorders, including excessive daytime sleepiness, cataplexy,narcolepsy, fatigue, depression, bipolar disorder, fibromyalgia, andothers.

Pharmacokinetic studies have demonstrated rapid absorption and high oralbioavailability of solriamfetol with dose-proportional exposure (maximumserum concentration and area under the concentration-time curve [AUC])in animals tested.

The present invention overcomes shortcomings in the art by providingmethods of administering solriamfetol to a lactating subject whilereducing the potential for adverse events from solriamfetol in an infantfed breast milk from the subject.

SUMMARY OF THE INVENTION

The present invention relates to the development of methods of reducingthe potential for adverse events from solriamfetol in an infant fedbreast milk from the subject. The invention additionally related to amethod of reducing exposure to solriamfetol in an infant fed breast milkobtained from a subject treated with solriamfetol.

Accordingly, one aspect of the invention relates to a method of reducingexposure to solriamfetol in an infant fed breast milk obtained from asubject treated with solriamfetol comprising: orally administering thesolriamfetol to the subject at a daily dose of about 37.5 mg to about300 mg; and feeding the infant breast milk from the subject at leastabout 5 hours after administering the solriamfetol to the subject,thereby reducing exposure to solriamfetol in the infant.

Another aspect of the invention relates to a method for decreasing thepotential for adverse events from solriamfetol in an infant fed breastmilk obtained from a subject treated with solriamfetol comprising:administering solriamfetol orally at a daily dose of between 37.5 mg and300 mg to the subject; and feeding the infant breast milk from thesubject at least about 5 hours after administering the solriamfetol tothe subject, thereby decreasing the potential for adverse events fromsolriamfetol in the infant. In some embodiments, the daily dose ofsolriamfetol is 150 mg.

An aspect of the invention relates to a method treating a disordertreatable with solriamfetol in a subject producing breast milk forfeeding an infant, comprising: administering solriamfetol orally at adaily dose of between 37.5 mg and 300 mg to the subject; and reducingexposure to solriamfetol and/or decreasing the potential for adverseevents in the infant fed breast milk from the subject comprising feedingthe infant breast milk from the subject at least about 5 hours afteradministering the solriamfetol to the subject. The disorder treatablewith solriamfetol can be, without limitation, narcolepsy, excessivedaytime sleepiness, obstructive sleep apnea, attentiondeficit/hyperactivity disorder, cognitive impairment or binge eatingdisorder.

In some embodiments, the method provides a daily infant dose ofsolriamfetol of about 0.3 mg or lower. In some embodiments, the methodachieves a relative infant dose of less than about 9% of the subjectweight-adjusted dose. In some embodiments, the method achieves arelative infant dose of less than about 5% of the subjectweight-adjusted dose.

In some embodiments, the infant does not experience agitation, insomnia,anorexia, or reduced weight gain due to solriamfetol exposure.

In some embodiments, the subject is from 1 day to 24 months postpartumor from 10 days to 12 months postpartum.

In some embodiments, the subject is being treated with solriamfetol fornarcolepsy, excessive daytime sleepiness, obstructive sleep apnea,attention deficit/hyperactivity disorder, cognitive impairment, or bingeeating disorder.

In some embodiments, the subject is a woman between the ages of 18 and45 years.

In some embodiments, the adverse events are one or more of agitation,insomnia, anorexia, or reduced weight gain.

Methods of treating a disorder amenable to treatment with solriamfetolin a subject who is breastfeeding an infant are provided comprisingorally administering solriamfetol at a daily dose of between about 37.5mg and 300 mg to the subject.

These and other aspects of the invention are set forth in more detail inthe description of the invention below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 . Time course of mean solriamfetol breast milk and plasmaconcentration-time profiles on linear and semi-logarithmic scales.

FIG. 2 . Mean breast milk cumulative solriamfetol amount-time profileson linear scale following a single-dose administration of solriamfetol150 mg tablet.

DETAILED DESCRIPTION

The present invention will now be described in more detail withreference to the accompanying drawings, in which preferred embodimentsof the invention are shown. This invention may, however, be embodied indifferent forms and should not be construed as limited to theembodiments set forth herein. Rather, these embodiments are provided sothat this disclosure will be thorough and complete, and will fullyconvey the scope of the invention to those skilled in the art. Inaddition, any references cited herein are incorporated by reference intheir entireties.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of skill in the artto which this invention belongs. The terminology used in the descriptionof the invention herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention.All publications, patent applications, patents, patent publications andother references cited herein are incorporated by reference in theirentireties for the teachings relevant to the sentence and/or paragraphin which the reference is presented.

Unless the context indicates otherwise, it is specifically intended thatthe various features of the invention described herein can be used inany combination.

Moreover, the present invention also contemplates that in someembodiments of the invention, any feature or combination of features setforth herein can be excluded or omitted.

To illustrate, if the specification states that a complex comprisescomponents A, B and C, it is specifically intended that any of A, B orC, or a combination thereof, can be omitted and disclaimed singularly orin any combination.

As used in the description of the invention and the appended claims, thesingular forms “a,” “an,” and “the” are intended to include the pluralforms as well, unless the context clearly indicates otherwise.

Also as used herein, “and/or” refers to and encompasses any and allpossible combinations of one or more of the associated listed items, aswell as the lack of combinations when interpreted in the alternative(“or”).

The term “about,” as used herein when referring to a measurable valuesuch as an amount of polypeptide, dose, time, temperature, enzymaticactivity or other biological activity and the like, is meant toencompass variations of ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of thespecified amount.

As used herein, the transitional phrase “consisting essentially of” (andgrammatical variants) is to be interpreted as encompassing the recitedmaterials or steps and those that do not materially affect the basic andnovel characteristic(s) of the claimed invention. Thus, the term“consisting essentially of” as used herein should not be interpreted asequivalent to “comprising.”

The term “therapeutically effective amount” or “effective amount,” asused herein, refers to that amount of a composition, compound, or agentof this invention that imparts a modulating effect, which, for example,can be a beneficial effect, to a subject afflicted with a disorder,disease or illness, including improvement in the condition of thesubject (e.g., in one or more symptoms), delay or reduction in theprogression of the condition, prevention or delay of the onset of thedisorder, and/or change in clinical parameters, disease or illness,etc., as would be well known in the art. For example, a therapeuticallyeffective amount or effective amount can refer to the amount of acomposition, compound, or agent that improves a condition in a subjectby at least 5%, e.g., at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, at least 45%, at least50%, at least 55%, at least 60%, at least 65%, at least 70%, at least75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least100%.

“Pharmaceutically acceptable carrier” (sometimes referred to as a“carrier”) refers to a carrier or excipient that is useful in preparinga pharmaceutical or therapeutic composition that is generally safe andnon-toxic and includes a carrier that is acceptable for veterinaryand/or human pharmaceutical or therapeutic use. The terms “carrier” or“pharmaceutically acceptable carrier” can include, but are not limitedto, phosphate buffered saline solution, water, emulsions (such as anoil/water or water/oil emulsion) and/or various types of wetting agents.As used herein, the term “carrier” encompasses, but is not limited to,any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer,lipid, stabilizer, or other material well known in the art for use inpharmaceutical formulations and as described further herein.

The term “modulate,” “modulates,” or “modulation” refers to enhancement(e.g., an increase) or inhibition (e.g., a decrease) in the specifiedlevel or activity.

The term “enhance” or “increase” refers to an increase in the specifiedparameter of at least about 1.25-fold, 1.5-fold, 2-fold, 3-fold, 4-fold,5-fold, 6-fold, 8-fold, 10-fold, twelve-fold, or even fifteen-foldand/or can be expressed in the enhancement and/or increase of aspecified level and/or activity of at least about 1%, 5%, 10%, 15%, 25%,35%, 40%, 50%, 60%, 75%, 80%, 90%, 95% or more.

“Inhibit” or “reduce” or grammatical variations thereof as used hereinrefers to a decrease or diminishment in the specified level or activityof at least about 1, 5, 10, 15%, 25%, 35%, 40%, 50%, 60%, 75%, 80%, 90%,95% or more. In particular embodiments, the inhibition or reductionresults in little or essentially no detectible activity (at most, aninsignificant amount, e.g., less than about 10% or even 5%).

“Treat,” “treating” and similar terms as used herein in the context oftreating a subject refer to providing medical and/or surgical managementof a subject. Treatment may include, but is not limited to,administering an agent or composition (e.g., a pharmaceuticalcomposition) to a subject. Treatment is typically undertaken in aneffort to alter the course of a disease (which term is used to indicateany disease, disorder, syndrome, or undesirable condition warranting orpotentially warranting therapy) in a manner beneficial to the subject.The effect of treatment may include reversing, alleviating, reducingseverity of, delaying the onset of, curing, inhibiting the progressionof, and/or reducing the likelihood of occurrence or recurrence of thedisease or one or more symptoms or manifestations of the disease. Atherapeutic agent may be administered to a subject who has a disease oris at increased risk of developing a disease relative to a member of thegeneral population. In some embodiments a therapeutic agent may beadministered to a subject who has had a disease but no longer showsevidence of the disease. The agent may be administered e.g., to reducethe likelihood of recurrence of evident disease. A therapeutic agent maybe administered prophylactically, i.e., before development of anysymptom or manifestation of a disease. “Prophylactic treatment” refersto providing medical and/or surgical management to a subject who has notdeveloped a disease or does not show evidence of a disease in order,e.g., to reduce the likelihood that the disease will occur, delay theonset of the disease, or to reduce the severity of the disease should itoccur. The subject may have been identified as being at risk ofdeveloping the disease (e.g., at increased risk relative to the generalpopulation or as having a risk factor that increases the likelihood ofdeveloping the disease.

Grammatical variations of “administer,” “administration,” and“administering” to a subject include any route of introducing ordelivering to a subject an agent. Administration can be carried out byany suitable route, including oral, topical, intravenous, subcutaneous,transcutaneous, transdermal, intramuscular, intra-joint, parenteral,intra-arteriole, intradermal, intraventricular, intracranial,intraperitoneal, intralesional, intranasal, rectal, vaginal, byinhalation, via an implanted reservoir, parenteral (e.g., subcutaneous,intravenous, intramuscular, intra-articular, intra-synovial,intrasternal, intrathecal, intraperitoneal, intrahepatic, intralesional,and intracranial injections or infusion techniques), and the like.“Concurrent administration,” “administration in combination,”“simultaneous administration,” or “administered simultaneously” as usedherein, means that the compounds are administered at the same point intime, overlapping in time, or one following the other. In the lattercase, the two compounds are administered at times sufficiently closethat the results observed are indistinguishable from those achieved whenthe compounds are administered at the same point in time. “Systemicadministration” refers to the introducing or delivering to a subject anagent via a route which introduces or delivers the agent to extensiveareas of the subject's body (e.g., greater than 50% of the body), forexample through entrance into the circulatory or lymph systems. Bycontrast, “local administration” refers to the introducing or deliveryto a subject an agent via a route which introduces or delivers the agentto the area or area immediately adjacent to the point of administrationand does not introduce the agent systemically in a therapeuticallysignificant amount. For example, locally administered agents are easilydetectable in the local vicinity of the point of administration but areundetectable or detectable at negligible amounts in distal parts of thesubject's body. Administration includes self-administration and theadministration by another.

“Pharmaceutically acceptable,” as used herein, means a material that isnot biologically or otherwise undesirable, i.e., the material can beadministered to an individual along with the compositions of thisinvention, without causing substantial deleterious biological effects orinteracting in a deleterious manner with any of the other components ofthe composition in which it is contained. The material would naturallybe selected to minimize any degradation of the active ingredient and tominimize any adverse side effects in the subject, as would be well knownto one of skill in the art (see, e.g., Remington's PharmaceuticalScience; 21st ed. 2005).

“Concurrently” means sufficiently close in time to produce a combinedeffect (that is, concurrently can be simultaneously, or it can be two ormore events occurring within a short time period before or after eachother). In some embodiments, the administration of two or more compounds“concurrently” means that the two compounds are administered closelyenough in time that the presence of one alters the biological effects ofthe other. The two compounds can be administered in the same ordifferent formulations or sequentially. Concurrent administration can becarried out by mixing the compounds prior to administration, or byadministering the compounds in two different formulations, for example,at the same point in time but at different anatomic sites or usingdifferent routes of administration.

“Bioavailability,” as used herein, refers to the estimated area underthe curve, or AUC of the active drug in systemic circulation after oraladministration with a dosage form as disclosed herein when compared withthe AUC of the active drug in systemic circulation after intravenousadministration of the active drug. The AUC is affected by the extent towhich the drug is absorbed in the GI tract.

Products are considered to be “bioequivalent” if the relative meanC_(max), AUC_((0-t)) and AUC_((0-∞)) of the test product to referenceproduct is within 80% to 125%.

The term “AUC_((0-t))” means the area under the plasma concentrationcurve from time 0 to time t.

The term “AUC_((0-t))” or “AUC_(0-inf)” means the area under the plasmaconcentration time curve from time 0 to infinity.

“C_(max)” refers to the maximum milk or plasma concentration ofsolriamfetol.

“T_(max)” refers to the time to maximum milk or plasma concentration fora given drug.

“t_(1/2)” refers to the time to reduce the milk and plasma concentrationby 50% during the terminal elimination phase of the drug.

Milk:plasma ratio means AUC in breast milk divided by AUC in plasma.

“A_(milk)” means the amount excreted in breast milk over 72 hours.

“Vd/F” means the apparent volume of distribution in plasma.

“CL/F” is the apparent oral clearance in plasma.

AUC0-t is the area under the concentration-time curve from time 0 to thetime t of the last quantifiable concentration (milk and plasma).

The present invention is based, in part, on methods of using Sunosi®(referred to herein as solriamfetol (also known as(R)-2-amino-3-phenylpropyl carbamate (APC), and previously known asJZP-110, ADX-N05, R228060, and YKP10A)) in lactating subjects with adisorder amenable to treatment with solriamfetol while reducing thepotential for adverse effects in infants fed the subject's breast milk.Administration of solriamfetol to subjects expressing breast milkpresents challenges. In a nonclinical study in rats, solriamfetol wasdetected in breast milk, with solriamfetol milk concentrations higherthan solriamfetol plasma concentrations. It is desirable to reduce orminimize any adverse effects from the daily dose received by an infantfed breast milk from a subject treated with solriamfetol. In addition,it is desirable to identify methods that allow for the safety andtolerability of solriamfetol in nursing subjects.

Accordingly, one aspect of the invention relates to a method of reducingexposure to solriamfetol in an infant fed breast milk obtained from asubject treated with solriamfetol comprising orally administering thesolriamfetol to the subject at a daily dose of about 37.5 mg to about300 mg; and feeding the infant breast milk from the subject at leastabout 5 hours after administering the solriamfetol to the subject,thereby reducing exposure to solriamfetol in the infant.

One aspect of the invention comprises methods for decreasing thepotential for adverse events from solriamfetol in an infant fed breastmilk obtained from a subject treated with solriamfetol comprisingadministering solriamfetol orally at a daily dose of between 37.5 mg and300 mg to the subject; and feeding the infant breast milk from thesubject at least about 5 hours after administering the solriamfetol tothe subject, thereby decreasing the potential for adverse events fromsolriamfetol in the infant. In an embodiment, the adverse event is oneor more of agitation, insomnia, anorexia, or reduced weight gain.

One aspect of the invention relates to a method for treating a disordertreatable with solriamfetol in a subject producing breast milk forfeeding an infant, comprising administering solriamfetol orally at adaily dose of between 37.5 mg and 300 mg to the subject; and reducingexposure to solriamfetol and/or decreasing the potential for adverseevents in the infant fed breast milk from the subject, comprisingfeeding the infant breast milk obtained from the subject at least about5 hours after administering the solriamfetol to the subject. In oneembodiment, the method reduces solriamfetol in the infant and the infantdoes not experience agitation, insomnia, anorexia, or reduced weightgain due to solriamfetol exposure. In one embodiment, the adverse eventsare one or more of agitation, insomnia, anorexia, or reduced weightgain.

A “disorder amenable to treatment with solriamfetol” or a “disordertreatable with solriamfetol” refers to any disorder in whichadministration of solriamfetol to a subject results in the treatment ofone or more symptoms of the disorder in the subject. Example disordersamenable to treatment with solriamfetol include narcolepsy, cataplexy,excessive daytime sleepiness, obstructive sleep apnea, drug addiction,sexual dysfunction, fatigue, fibromyalgia, attentiondeficit/hyperactivity disorder (ADHD), cognitive impairment and/orcognitive dysfunction, restless legs syndrome, depression, bipolardisorder, obesity, or binge eating disorder. In some embodiments, thedisorders amenable to treatment with solriamfetol include narcolepsy,excessive daytime sleepiness, obstructive sleep apnea, cognitiveimpairment, attention deficit/hyperactivity disorder, or binge eatingdisorder. See, for example, U.S. Pat. Nos. 8,232,315; 8,440,715;8,552,060; 8,623,913; 8,729,120; 8,741,950; 8,895,609; 8,927,602;9,226,910; and 9,359,290; and U.S. Publication Nos. 2012/0004300 and2015/0018414. All of the above patents and applications are herebyincorporated by reference in their entireties for all purposes.

“Excessive daytime sleepiness” or “EDS” refers to persistent sleepinessat a time when the individual would be expected to be awake and alert,even during the day after apparently adequate or even prolongednighttime sleep. EDS may be the result of a sleep disorder or a symptomof another underlying disorder such as narcolepsy, sleep apnea,circadian rhythm sleep disorder, or idiopathic hypersomnia. While thename includes “daytime,” it is understood that the sleepiness may occurat other times that the subject should be awake, such as nighttime orother times, e.g., if the subject is working nightshift. It is alsounderstood that EDS is medically distinct from fatigue and disordersassociated with fatigue.

In some embodiments, the cause of the EDS may be, without limitation,central nervous system (CNS) pathologic abnormalities, stroke,narcolepsy, idiopathic CNS hypersomnia; sleep deficiency, sleep apnea,obstructive sleep apnea, insufficient nocturnal sleep, chronic pain,acute pain, Parkinson's disease, urinary incontinence, multiplesclerosis fatigue, attention deficit hyperactivity disorder (ADHD),Alzheimer's disorder, major depression, bipolar disorder, cardiacischemia; misalignments of the body's circadian pacemaker with theenvironment, jet lag, shift work, or sedating drugs.

In certain embodiments, solriamfetol structure is given below as formulaI:

Methods for producing solriamfetol and related compounds can be found inU.S. Pat. Nos. 5,955,499; 5,705,640; 6,140,532 and 5,756,817. All of theabove patents and applications are hereby incorporated by reference intheir entireties for all purposes.

In one embodiment, the methods detailed herein provide an infant fedbreast milk from a subject to whom solriamfetol is administered does notexperience adverse events, e.g., agitation, insomnia, anorexia, orreduced weight gain due to solriamfetol exposure. Monitoring the infantfor agitation, insomnia, anorexia, or reduced weight gain can beperformed. For example, monitoring and/or detecting weight loss, reducedweight gain, reduction in number of feedings or lessened intake,reduction in volume of milk ingested can be performed. Monitoringincrease in agitation and/or insomnia in the infant, including areduction of sleeping hours and/or time to fall asleep and stay asleepcan also be performed to identify changes in the infant. In someembodiments, the monitoring for changes in the infant is performed at 3or more hours subsequent to administering of the solriamfetol dose andsubsequent to initiation of infant feeding with breast milk from thesubject, for example at 3 hours, 4, hours, 5 hours, 6 hours, 7 hours, 8hours, 9 hours, 10 hours or more subsequent to administering of thesolriamfetol dose. Monitoring for any changes experienced by the infant(e.g., agitation, insomnia, anorexia, or reduced weight gain) can beperformed over the time period in which solriamfetol is administered tothe subject, which may be over days, weeks, or months, with monitoringover any interval in that time frame, including hourly, daily, weekly,monthly or any time range therein.

In one embodiment, the method provides a daily infant dose ofsolriamfetol of about 0.3 mg or lower, e.g., about 0.29 mg, about 0.28mg, about 0.27 mg, about 0.26 mg, about 0.25 mg, about 0.24 mg, about0.23 mg, about 0.22 mg, about 0.21 mg, about 0.20 mg, about 0.19 mg,about 0.18 mg, about 0.17 mg, about 0.16 mg, about 0.15 mg, or lower.The daily infant dose means the daily dose that was received by theinfant through feeding of breast milk.

In some embodiments, breast milk for feeding of the infant is expressedor produced from the subject at 3 or more hours, 4 or more hours, or 5or more hours, for example at 3 hours, 4, hours, 5 hours, 6 hours, 7hours, 8 hours, 9 hours, 10 hours or more, subsequent to administeringof the solriamfetol dose to the subject. In some embodiments, the breastmilk produced from the subject for infant feeding in the methodsdetailed herein occurs at about the mean elimination half-life ofsolriamfetol or later, i.e., at about 5 hours, subsequent toadministration of the solriamfetol. In some embodiments, thebreastfeeding of the infant is performed at 3 or more hours, 4 or morehours, or 5 or more hours subsequent to administering of thesolriamfetol dose to the subject. In some embodiments, the breast milkfor feeding the infant is obtained from the subject at 3 or more hours,4 or more hours, or 5 or more hours subsequent to administering of thesolriamfetol dose to the subject.

In some embodiments, the method achieves a relative infant dose, thepercentage of the weight-adjusted subject dose excreted in breast milkover 24 hours, of less than about 10%, less than about 9.5%, less thanabout 9%, less than about 8.5%, less than about 8%, less than about7.5%, less than about 7%, less than about 6.5%, less than about 6%, lessthan about 5.5%, less than about 5%, less than about 4.9%, less thanabout 4.8%, less than about 4.7%, less than about 4.6%, less than about4.5%, less than about 4.4%, less than about 4.3%, less than about 4.2%,less than about 4.1%, or about 4.0% of the subject weight-adjusted dose.

In some embodiments, the average amount of solriamfetol that would bepassed to an infant feeding from the breast milk produced by the subjecttreated with solriamfetol according to the methods disclosed herein isless than about 0.70 mg, about 0.69 mg, about 0.68 mg, about mg, about0.66 mg, about 0.65 mg, about 0.64 mg, about 0.63 mg, about 0.62 mg,about mg, about 0.60 mg, or about 0.59 mg over 24 hours.

A daily dose of about 1 to about 2000 mg of solriamfetol or apharmaceutically acceptable salt thereof may be administered toaccomplish the therapeutic results disclosed herein. For example, adaily dosage of about 1-1000 mg, e.g., about 20-500 mg, in single ordivided doses, is administered. In some embodiments, the daily dose maybe about 0.01 to about 150 mg/kg body weight, e.g., about 0.2 to about18 mg/kg body weight. In some embodiments, the dose contains about 1 mgto about 1000 mg of the drug or any range or value therein, e.g., about10 mg to about 500 mg, e.g., about 37.5 mg, about 75 mg, about 150 mg,or about 300 mg. For example, in certain such embodiments, the totalamount of drug may be selected from about 20, 30, 40, 50, 60, 70, 80,90, 100, 125, 150, 175, 200, 225, 250, 275, 300, or any range therein.

In one embodiment of the invention, solriamfetol is administered to thesubject as needed to treat a disorder. The compound can be administeredcontinuously or intermittently. In one embodiment, the compound isadministered to the subject more than once a day, e.g., 2, 3, or 4 timesper day, or once every 1, 2, 3, 4, 5, 6, or 7 days. In anotherembodiment, the compound is administered to the subject no more thanonce a week, e.g., no more than once every two weeks, once a month, onceevery two months, once every three months, once every four months, onceevery five months, once every six months, or longer. In a furtherembodiment, the compound is administered using two or more differentschedules, e.g., more frequently initially (for example to build up to acertain level, e.g., once a day or more) and then less frequently (e.g.,once a week or less). In other embodiments, the compound can beadministered by any discontinuous administration regimen. In oneexample, the compound can be administered not more than once every threedays, every four days, every five days, every six days, every sevendays, every eight days, every nine days, or every ten days, or longer.The administration can continue for one, two, three, or four weeks orone, two, or three months, or longer. Optionally, after a period ofrest, the compound can be administered under the same or a differentschedule. The period of rest can be one, two, three, or four weeks, orlonger, according to the pharmacodynamic effects of the compound on thesubject. In another embodiment the compound can be administered to buildup to a certain level, then maintained at a constant level and then atailing dosage.

In one aspect of the invention, solriamfetol is delivered to a subjectconcurrently with an additional therapeutic agent. The additionaltherapeutic agent can be delivered in the same composition as thecompound or in a separate composition. The additional therapeutic agentcan be delivered to the subject on a different schedule or by adifferent route as compared to the compound. The additional therapeuticagent can be any agent that provides a benefit to the subject. Furtheragents include, without limitation, stimulants, anti-psychotics,anti-depressants, agents for neurological disorders, andchemotherapeutic agents. One therapeutic agent that can be administeredduring the same period is Xyrem®, sold commercially by JazzPharmaceuticals, which is used to treat narcolepsy and cataplexy. SeeU.S. Pat. Nos. 8,952,062 and 9,050,302.

The present invention finds use in research as well as veterinary andmedical applications. Suitable subjects are generally mammaliansubjects. The term “mammal” as used herein includes, but is not limitedto, humans, non-human primates, cattle, sheep, goats, pigs, horses,cats, dog, rabbits, rodents (e.g., rats or mice), etc. Human subjectsinclude neonates, infants, juveniles, adults, and geriatric subjects. Insome embodiments, the subject is postpartum, In some embodiments, thesubject is a woman between the ages of 18 and 45 years.

Suitable subjects are generally lactating mammalian subjects. The term“mammal” as used herein includes, but is not limited to, humans,non-human primates, cattle, sheep, goats, pigs, horses, cats, dog,rabbits, rodents (e.g., rats or mice), etc. The human subject can be alactating individual who is breastfeeding an infant frequently or on aregular basis. In some embodiments, the human subject is a woman. Thewoman may be between about 18 and 45 years of age. The term“breastfeeding” may also be referred to as chestfeeding, or grammaticalvariations thereof, refers to delivering breast milk of the individualdirectly to an infant, extracting breast milk from the individual usinga device and subsequently delivering to an infant, extracting breastmilk from the individual using a device and storing the breast milk fora period of time and subsequently delivering the stored breast milk tothe infant, or a combination thereof.

The subject of the present disclosure can be in lactation, for example,an individual who is lactating (e.g., producing breast milk), nursing orbreastfeeding. The subject can be in lactation after pregnancy, i.e.,post-partum, or via induced lactation (e.g., with metoclopramide, oralcontraceptives, herbal medications, stimulation via pumping, or anycombination thereof).

In some embodiments, the subject is between 1 day and 24 monthspostpartum, between about 1 day and 12 months postpartum, or betweenabout 10 days and 12 months postpartum. In some embodiments, the subjectexpresses mature milk, which typically occurs about 10 to about days(e.g., about 10 days, about 11 days, about 12 days, about 13 days, about14 days, about days, about 16 days, about 17 days, about 18 days, about19 days, about 20 days, about 21 days, about 22 days, about 23 days,about 24 days, about 25 days, about 26 days, about 27 days, about 28days, about 29 days, about 30 days) postpartum, or about 10 to about 20days postpartum, or about 10 to about 20 days after beginning of milkexpression in induced lactation. Infancy starts at birth and ends aroundthe age of 2 years; accordingly, the infant stage being fed breast milkincludes the breastfeeding period.

The subject can be a subject “in need of” the methods of the presentinvention, e.g., in need of the therapeutic effects of the inventivemethods. For example, the subject can be a subject that is experiencinga disorder amenable to treatment with solriamfetol, is suspected ofhaving a disorder amenable to treatment with solriamfetol, and/or isanticipated to experience a disorder amenable to treatment withsolriamfetol, and the methods and compositions of the invention are usedfor therapeutic and/or prophylactic treatment.

Having described the present invention, the same will be explained ingreater detail in the following examples, which are included herein forillustration purposes only, and which are not intended to be limiting tothe invention.

EXAMPLES Example 1. Phase 4 Clinical Trial In Breastfeeding Subjects

A Phase 4, open-label, single-dose study to evaluate thepharmacokinetics (PK) of solriamfetol in the breast milk and plasma ofhealthy postpartum women following oral administration of a 150 mgsolriamfetol tablet.

The study was conducted in 6 healthy adult lactating women who werebetween 15 and 37 weeks postpartum and were administered a single oraldose of SUNOSI 150 mg. SUNOSI was excreted in breast milk with a milk toplasma AUC ratio of approximately 2:1. The median T_(max) for SUNOSI inbreast milk was approximately 1.1 hours, and the mean eliminationhalf-life in breast milk was approximately 5.0 hours. The average amountthat would be passed to the infant was estimated to be 0.59 mg over 24hours, which is about 4.0% of the maternal dose on a weight-adjustedbasis. The data from the lactation study indicate that SUNOSI istransferred to breastmilk in nursing mothers, with the relative infantdose (RID) is approximately 4% of the maternal weight-adjusted dosage.Data to assess the effects of SUNOSI on a breastfed infant or on milkproduction is not provided. The developmental and health benefits ofbreastfeeding should be considered along with the mother's clinical needfor SUNOSI and any potential adverse effects on the breastfed child fromSUNOSI or from the underlying maternal condition. Breastfed infantsshould be monitored for adverse reactions, such as agitation, insomnia,anorexia, and reduced weight gain.

Solriamfetol had a short systemic elimination half-life of 5.0 to 7.6hours, and with once daily dosing the estimated accumulation ratio of1.06 was marginally higher than 1, indicating essentially noaccumulation with repeated dosing. Therefore, a single therapeutic doseof solriamfetol was administered in this study. Since the objective ofthis study was to evaluate solriamfetol PK in breast milk and plasma, aswell as to estimate the daily drug dose received by the infant frombreast milk, the highest approved therapeutic dose of 150 mgsolriamfetol was administered.

The subjects were between 10 days and 52 weeks postpartum. The lowertime limit of days postpartum represented a time after which mature milkwas developed (US FDA 2019). The upper time limit of 52 weeks postpartumwas chosen based on a prospective study that showed that fat, totalsolids, and “energy” (kcal/dL) were all statistically increased inbreast milk collected 12 to 18 months postpartum (N=25) compared withbreast milk collected 1 to 12 months postpartum (N=35) (CzosnykowskaLukacka 2018). Also, there was a paucity of data regarding breast milknutrient composition at >12 months postpartum (Wu 2018). The studyincluded frequent maternal milk sample collections during a 72-hourperiod postdose to enable detection of the potential presence ofsolriamfetol in breast milk. Plasma concentrations of solriamfetol werealso evaluated during the same time period to assess solriamfetol'spotential accumulation in breast milk relative to the plasma.

Subjects were instructed to refrain from breastfeeding their infants for72 hours postdose. Based on the drug's short half-life, this period(10×half-life) was expected to be of sufficient duration for completeelimination of solriamfetol from both the systemic circulation andbreast milk.

Pharmacokinetic Results

All subjects in the PK Population were included in the PK analysis.Pharmacokinetic Population was defined as all subjects who receivedstudy drug and provided postdose breast milk or plasma PK data for atleast one collection interval or time point. Subject 1003, 1004, and1007 had multiple protocol deviations documented with regards to thetiming of food consumption, however, these deviations are not likely toimpact solriamfetol PK and these subjects were included in thedescriptive statistics or PK parameter analysis. Furthermore, the PK ofsolriamfetol in fed versus fasted subjects satisfied the criteria forbioequivalence, indicating that solriamfetol can be taken regardless offood intake.

The mean plasma and breast milk solriamfetol concentration time profilesare shown in FIG. 1 . FIG. 1 shows the time course of mean plasma andbreast milk solriamfetol concentrations on Day 1 following a single-doseadministration of solriamfetol 150 mg tablet in the morning 2 hoursafter completion of a light breakfast. After reaching maximumsolriamfetol concentrations approximately 1.00 to 3.00 hours after oraladministration, plasma and breast milk exposures followed a parallelmonoexponential decline. Solriamfetol concentrations in breast milk wereapproximately 2-fold higher than plasma concentrations

The mean breast milk cumulative solriamfetol amount-time profiles areshown in FIG. 2 . FIG. 2 shows the mean breast milk cumulativesolriamfetol amount-time profiles following a single-dose administrationof solriamfetol 150 mg tablet in the morning 2 hours after completion ofa light breakfast. Arithmetic mean±SD amount excreted in breast milkover 72 hours was mg. However, near complete excretion was observedwithin 24 hours of dosing.

No subjects had Rsq adjusted values <0.700, or % AUCex>20%, thereforeLambda_z and AUC0-inf related parameters were all considered reliableand included in descriptive statistics.

Table 1 summarizes the plasma and breast milk PK parameters forsolriamfetol following single-dose administration.

Solriamfetol exposure was approximately 2-fold higher, on average, inbreast milk than plasma with geometric mean C_(max) of 1861 vs 892.5ng/mL, AUC_(0-t) of 12770 vs 6236 h*ng/mL, and AUC_(0-inf) of 12940 vs6340 h*ng/mL, respectively. The geometric mean milk:plasma ratio was2.047.

Plasma solriamfetol t_(max) (from 0.98 to 3.02 hours, median 1.25 hours)was similar to breast milk (from 1.00 to 3.00 hours, median 1.12 hours).

The geometric mean solriamfetol t_(1/2) appear similar between plasma(4.751 hours) and breast milk (4.869 hours). Furthermore, the geometricmean plasma solriamfetol CL/F was 23.66 L/h and V_(z)/F was 162.2 L.Geometric mean A_(milk) (was 0.5651 mg, with a daily and relative infantdose of 0.5856 mg and 4.030%, respectively.

TABLE 1 Summary of Pharmacokinetic Parameters for Solriamfetol in Plasmaand Breast Milk (Pharmacokinetic Population) Arithmetic Mean (CV %)[Geometric Mean] Pharmacokinetic Plasma Breast Milk Parameters (N = 6)(N = 6) AUC_(0-inf) (h * ng/mL) 6543 (27.7) [6340] 13850 (41.0) [12940]AUC_(0-t) (h * ng/mL) 6439 (27.9) [6236] 13700 (41.4) [12770] C_(max)(ng/ml) 905.2 (18.0) [892.5] 2068 (48.7) [1861] t_(max) (h)^(a) 1.25(0.98, 3.02) 1.12 (1.00, 3.00) Lambda_z (1/h) 0.1478 (19.1) [0.1459]0.1446 (18.8) [1424] t_(1/2) (h) 4.804 (15.2) [4.751] 4.954 (21.4)[4.869] CL/F (L/h) 24.40 (26.8) [23.66] NC V_(z)/F (L) 168.9 (31.9)[162.2] NC Milk:Plasma Ratio NC 2.136 (35.8) [2.047] A_(milk) (mg) NC0.6880 (67.9) [0.5651] Daily Infant Dose NC 0.6927 (63.5) [0.5856] (mg)NC 4.602 (60.6) [4.030] Relative Infant Dose (%) NC = not calculated.Note: CV % was based on the arithmetic mean. ªMedian (min, max).Pharmacokinetic Conclusion

Solriamfetol t_(max) for both plasma and breast milk were similar andranged between 1 to 3 hours. After reaching maximum solriamfetolconcentrations, plasma and breast milk exposures followed a parallelmonoexponential decline. Solriamfetol breast milk exposure (C_(max) andAUCs) was 2-fold higher than plasma. Furthermore, the geometric meanmilk:plasma ratio was 2.047. The solriamfetol t_(1/2) appeared similarin plasma and breast milk at approximately 5 hours. This study wasexclusively in post-partum women, a very different population than theones for the studies reported in the Pharmacokinetics section of thecurrent Sunosi® label which were healthy male and female patients whowere not postpartum. The Sunosi® label reports oral bioavailability ofsolriamfetol is approximately 95% with peak plasma concentration ofsolriamfetol occurs at a median T. of 2 hours (range 1.25 to 3.0 hours)post-dose under fasted conditions healthy male and female patients whowere not postpartum. Indeed, while the median T_(max) reported forhealthy male and female patients who were not postpartum is reported inthe label as 2 hours, the T_(max) in the present lactation study is 1hour. Similarly, the apparent mean elimination plasma half-life is 7.1hours for healthy male and female patients who were not postpartum onthe Sunosi® label compared to 4.8 hours in plasma and 4.95 hours inbreast milk in the present lactation study.

CL/F and were determined for plasma solriamfetol only. Arithmetic meanof CL/F was 24.40 L/h and was 168.9 L. A_(milk), daily infant dose, andrelative infant dose were determined for breast milk solriamfetol only.Arithmetic mean of was 0.6880 mg, daily infant dose was 0.6927 mg, andrelative infant dose was 4.602% Safety Results

Adverse Events: The overall summary of Treatment Emergent Adverse Events(TEAEs) is summarized in Table 2. A total of 3 (50%) subjects had atleast 1 AE; of 2 (33.3%) subjects had TEAEs related to the study drugand 1 (16.7%) subject had TEAE unrelated to the study drug. The mildTEAEs were reported in 2 (33.3%) subjects and moderate TEAEs werereported in 1 (16.7%) subject. No SAEs were reported in the study. Noneof the subjects discontinued due to TEAEs.

TABLE 2 Overall Summary of Treatment Emergent Adverse Events (SafetyPopulation) Solriamfetol 150 mg (N = 6) Category n (%) Subjects with atleast 1 AE 3 (50.0) Subjects with an AE considered related to study drug2 (33.3) AE considered unrelated to study drug 1 (16.7) Subjectswith^(a) SAE 0 SAE considered related to study drug 0 SAE consideredunrelated to study drug 0 Subjects who discontinued due to AE 0 AEconsidered related to study drug 0 AE considered unrelated to study drug0 Subjects with^(a) Mild AE 2 (33.3) Moderate AE 1 (16.7) Severe AE 0Life-threatening AE 0 Fatal AE 0 AE = adverse event; N = number ofsubjects exposed; SAE = serious adverse event. Note: Percentages arebased on N ªSubjects reporting an adverse event in more than onecategory were counted only once for the category.

Out of 3 subjects reporting TEAEs, 1 subject had dizziness and headache(SOC: Nervous system disorder), 1 subject had agitation (SOC:Psychiatric disorder), and 1 subject had an event of headache (SOC:Nervous system disorder) (Table 3). A total of 4 TEAEs were reportedwhere 3 TEAEs (dizziness, headache, and agitation) were mild and 1 TEAE(headache) was moderate in intensity. All the 3 mild TEAEs were relatedto the study drug and the moderate TEAE was unrelated to the study drug.All the TEAEs were resolved.

TABLE 3 Summary of Treatment Emergent Adverse Events by System OrganClass, Preferred Term (Safety Population) System Organ SolriamfetolClass (SOC) 150 mg Preferred Term (N = 6) (PT) n (%) Nervous system 2(33.3) disorders Dizziness 1 (16.7) Headache 2 (33.3) Psychiatric 1(16.7) disorders Agitation 1 (16.7) N = number of subjects exposed.Notes: Percentages are based on N. A subject with multiple adverseevents within a primary system organ class was counted only once. Asubject with multiple occurrences of an AE was counted only once in theAE category System organ classes are presented in alphabetical order;preferred terms are presented within system organ class in alphabeticalorder Adverse events were coded using the MedDRA coding dictionary,MedDRA180 Mixed

Vital Signs: There were no major changes in vital sign parameters frombaseline to Day 1 2 hours and 4 hours, Day 2, Day 3, and Day 4. Thesummary of clinically notable vital signs at any post-baseline visit aresummarized in Table 4.

TABLE 4 Summary of Clinically Notable Vital Signs at Any Post-baselineVisit/Timepoint (Safety Population) Solriamfetol 150 mg (N = 6)Parameter (Unit) Criteria n (%) Systolic blood Blood pressure changeby >20% from 1 (16.7) pressure (mmHg) the study baselinevalue/recordings Diastolic blood Average diastolic blood pressure 2(33.3) pressure (mmHg) ≥95 mmHg or ≤60 mmHg Pulse rate Pulse changeby >20% from the study 2 (33.3) (beats/min) baseline value/recordingsBody Change in body temperature >1.8% 1 (16.7) temperature (C.) from thesubjects baseline temperature recordings N = number of subjects exposed.Notes: Percentages are based on N. Baseline was defined as the lastnon-missing measurement taken prior to dosing. All post-baselineassessments, including unscheduled, were considered for this summary.

There were no major changes in ECG parameters from baseline to Day 1predose and 2 hours, Day 2, Day 3, and Day 4. No abnormal clinicallysignificant ECG findings were reported.

The summary of clinically notable ECG findings at any post-baselinevisit are summarized in Table 5.

TABLE 5 Summary of Clinically Notable Electrocardiograms at AnyPost-baseline Visit/Timepoint (Safety Population) Solriamfetol 150 mg (N= 6) Parameter (Unit) Criteria n (%) ECG mean heart Ventricular rate≥100 beats/min 2 (33.3) rate (bpm) or ≤60 beats/min PR interval, singlePR interval ≥200 msec 2 (33.3) beat (msec) or ≤120 msec QRS duration,QRS duration ≥100 msec 4 (66.7) single beat (msec) or ≤80 msec QTinterval, QT interval ≥440 msec 1 (16.7) single beat (msec) or ≤350 msecN = number of subjects exposed. Notes: Percentages are based on N.Baseline was defined as the last non-missing measurement taken prior todosing. All post-baseline assessments, including unscheduled, wereconsidered for this summary.

None of the subjects had reported any suicidal ideation or event underColumbia-Classification Algorithm for Suicide Assessment.

Safety Conclusions

Overall, 6 subjects were enrolled in the safety analysis and treatedwith the single oral dose of Solriamfetol which was safe and welltolerated.

Out of 6 subject 3 (50%) subjects had at least 1 AE. Out of 3 subjectsreporting TEAEs: 1 subject had dizziness and headache (SOC: Nervoussystem disorder) both of mild intensity and were related to study drug;1 subject had agitation (SOC: Psychiatric disorder) of mild intensityand was related to study drug; 1 subject had an event of headache (SOC:Nervous system disorder) of moderate intensity and was not related tostudy drug. No SAEs, deaths, or other significant AEs were reported inthe study. None of the subjects discontinued due to TEAEs. None of thesubjects had abnormal, clinically significant laboratory findings. Therewere no major changes in vital sign from baseline to Day 1 2 hours and 4hours, Day 2, Day 3, and Day 4 and ECG parameters from baseline to Day 1predose and 2 hours, Day 2, Day 3, and Day 4. None of the subjects hadreported any suicidal ideation or event under Columbia-ClassificationAlgorithm for Suicide Assessment.

Discussion

The instant study was a Phase 4, open-label, single-dose study toevaluate the PK of solriamfetol in the breast milk and plasma of healthypostpartum women following oral administration of a 150 mg solriamfetoltablet. A total of 6 subjects were enrolled and were included in both PKand safety analysis. All the 6 subjects had completed the study. Therewere no premature discontinuations reported in the study.

The primary objective (PK) of this study was to assess the PK ofsolriamfetol in plasma and breast milk after single oral dose ofsolriamfetol 150 mg tablet in the morning 2 hours after completion of alight breakfast. Solriamfetol exposure was approximately 2-fold higher,on average, in breast milk than plasma with geometric mean C_(max) of1861 vs 892.5 ng/mL, AUC_(0-t) of 12770 vs 6236 h*ng/mL, and AUC_(0-inf)of 12940 vs 6340 h*ng/mL, respectively. The geometric mean milk:plasmaratio was 2.047. Plasma solriamfetol t_(max) (from 0.98 to 3.02 h,median 1.25 h) was similar to breast milk (from 1.00 to 3.00 hours,median 1.12 hours). The geometric mean solriamfetol t_(1/2) appearedsimilar between plasma (4.751 hours) and breast milk (4.869 hours).Furthermore, the geometric mean plasma solriamfetol CL/F was 23.66 L/hand V_(z)/F was 162.2 L. Geometric mean A_(milk) was 0.5651 mg, with adaily and relative infant dose of 0.5856 mg and 4.030%, respectively.

The secondary objective of study was to assess the safety andtolerability of the solriamfetol in healthy postpartum women. Overall,the study drug was safe and well tolerated. No SAEs, deaths, or othersignificant AEs were reported in the study. None of the subjectsdiscontinued due to TEAEs. Out of 6 subjects, 3 subjects reportedadverse events. All AE (dizziness, headache, and agitation) were of mildintensity except 1 AE (headache) was of moderate intensity.

None of the subjects had abnormal or clinically significant laboratoryfindings. There were no major changes in vital sign from baseline to Day1 2 hours and 4 hours, Day 2, Day 3, and Day 4 and ECG parameters frombaseline to Day 1 predose and 2 hours, Day 2, Day 3, and Day 4. None ofthe subjects had reported any suicidal ideation or event underColumbia-Classification Algorithm for Suicide Assessment.

Conclusion

Solriamfetol T_(max) for both plasma and breast milk were similar andranged between 1 to 3 hours. After reaching maximum solriamfetolconcentrations, plasma and breast milk exposures followed a parallelmonoexponential decline. Solriamfetol breast milk exposure (C_(max),AUCs) was 2-fold higher than plasma. Furthermore, the geometric meanmilk:plasma ratio was 2.047. Solriamfetol t_(1/2) appeared similar inplasma and breast milk at approximately 5 hours. Solriamfetol was safeand well tolerated.

Methodology

On Day −1, eligible subjects underwent the baseline procedures. On Day1, 2 hours after a light breakfast, subjects were to receive a singledose of solriamfetol 150 mg with 240 mL of water. Subjects had to fastfor approximately 4 hours after the first dose; water was allowed exceptfor 1 hour before and 1 hour after dosing with the study drug.

Pharmacokinetic analysis of breast milk obtained from both breasts (bypumping) was evaluated prior to dose administration and at intervals upto 72 hours postdose. Blood samples were also collected for plasmasolriamfetol quantitation and PK analysis predose and at timepoints upto 72 hours postdose. Solriamfetol breast milk and plasma concentrationswere measured using validated bioanalytical methods. Safety was assessedthroughout the study by 12-lead ECG, vital sign measurements, theColumbia-Suicide Severity Rating Scale (C-SSRS), and the incidence ofadverse events (AE).

The study drug was yellow, film-coated tablets that contained theexcipients hydroxypropyl cellulose and magnesium stearate and a polymerfilm coat (Opadry®).

The total overall study duration (first subject screened to safetyfollow-up of last subject) was approximately 11 months.

Vital signs (blood pressure, pulse rate, temperature, and respiratoryrate) were measured with the subject in a seated or supine position andresting for at least 5 minutes prior to taking the measurement. Thedominant arm was used for blood pressure and pulse rate measurements. OnDay 1, vital signs were collected at predose, and at approximately 2(blood pressure and pulse) and 4 hours (blood pressure and pulse)postdose.

12-lead ECG was taken with the subject in a supine position and restingfor at least 10 minutes prior to taking the measurement. On Day 1, ECGswere collected predose and at approximately 2 hours postdose.

Subjects must fast for at least 8 hours before chemistry and hematologyblood draws. All clinical laboratory tests were performed at Screeningonly (rescreening is permitted).

Screening/Baseline C-SSRS version at Screening, and since Last Visitversion on Day −1 and Day 2 (or at ET).

Breast milk collection occurred at −2 to 0 (prior to dose), 0-2, 2-4,4-8, 8-12, 12-18, 24-32, 32-40, 40-48 and 48-72 hours postdose on Days1-4.

Blood samples for plasma PK evaluation were collected at the followingtime points: Predose, 1, 1.5, 3, 6, 8.5, 10, 13, 15, 21, 24, 28, 36, 44,and 72 hours following dosing on Day 1. General study methodology isoutlined in Table 6.

TABLE 6 Check-in Study drug Check- Safety Lactation Screening (Baseline)dosing out Follow-up Follow-up PK sampling Days −21 Day −1 Day 1 Day 4Days 9-11 Days 39-41 to −2

Standardized meals include meals as needed on Day −1, a light breakfastapproximately 2.5 hours before dosing on Day 1 (to be completedapproximately 2 hours before dosing) followed by lunch approximately 4hours after dosing, dinner approximately 8 hours after dosing, and asnack approximately 11 hours after dosing, and standardized mealsthereafter.

Record was from 30 days prior to screening through the Safety Follow Uptelephone call 5 to 7 days after check-out from the study facility (atDay 4 or ET).

Adverse events were monitored throughout the study by safetyassessments, observations, and subject reporting, including the SafetyFU telephone call 5-7 days (i.e., Days 9-11) after check-out from thestudy facility on Day 4, or ET.

Breast milk collection: Solriamfetol concentration in breast milk andplasma was evaluated based on samples collected prior to and postdose onDays 1 to 4. Breast milk was collected from both breasts, usingelectronic breast pumps, during the following intervals: From −2 to 0 atpredose and at 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 18, 18 to 24, 24to 32, 32 to 40, 40 to 48, and 48 to 72 hours postdose on Day 1. Themidpoint of each breast milk collection interval was used as the timevariable.

Breast milk was collected as often as needed during the assignedintervals; however, at the end of each interval, breast milk was pumpedfrom both breasts and collected. At the end of each collection interval,all milk expressed from both breasts during that interval was pooled.The milk was thoroughly mixed by gently inverting the collection vessel10 times to ensure homogeneity in milk composition. The weight andvolume of the collected milk during each interval was also recorded.

Serial blood samples (4 mL) were collected and dispensed into labeledK2EDTA tubes. The actual time of blood collection for all samples wasrecorded on the eCRF. Solriamfetol concentration in breast milk andplasma were determined using a validated bioanalytical method (LC-MS/MS)at Origin Bioanalytical Laboratory. The analytical range (lower limit ofquantitation [LLOQ] to upper limit of quantitation) for plasmasolriamfetol was 8.42 to 4210.00 ng/mL, and breast milk solriamfetol was10.0 to 8000 ng/mL.

Pharmacokinetic parameters were derived with Phoenix® WinNonlin® Version8.3 (Certara, Inc., Princeton, New Jersey, USA) and/or SAS ° Version 9.4(SAS Institute, Inc., Cary, North Carolina, USA).

Criteria for Subjects: Each subject who met the following criteria wereenrolled in the study: Healthy adult female 18 to 50 years of age,inclusive, at the time of consent; At least 50 kg body weight and bodymass index (BMI) within 18 to 35 kg/m 2 inclusive; Postpartum between 10days and 52 weeks, inclusive, after delivery of a normal, healthy infantby the time of dosing, and actively lactating from both breasts; Ifbreastfeeding, agreed to withhold breastfeeding their infant(s) fromapproximately 2 hours before dosing to approximately 72-hours afterdosing and resumed breastfeeding after completion of study Day 4procedures or would have made a decision to wean their infants beforeenrollment in the study; Agreed not to use nicotine-containing productsincluding tobacco (cigarettes, cigars, chewing tobacco, snuff),e-cigarettes, and nicotine lozenge/gum/patch within 3 days prior tocheck-in on Day −1, and for the duration of the study; Had used amedically acceptable method of contraception for at least the 2 monthsprior to dosing on Day 1, and consented to use a medically acceptablemethod of contraception throughout the entire study period and for 30days after the study was completed; Agreed to comply withstudy-specified diet while in the study; Able to understand and complywith study requirements; Ensured that their breastfed infant(s) was ableto feed from a bottle before study participation begins; Agreed toensure nutrition was available for their infant(s) through stored breastmilk, or alternative nutritional sources as necessary, for the durationof the study; Participants who: Were fully vaccinated for at least 14days after the last (or only) dose of the severe acute respiratorysyndrome coronavirus 2 (SARS-CoV-2 [COVID-19]) vaccine; or Elected notto be vaccinated prior to the study, with Participant who chooses not tobe fully vaccinated prior to the start of the study did not receive anydose of the COVID-19 vaccine and remained on the study.

Clinical laboratory tests including hematology, serum chemistry,urinalysis. and thyroid panel, were collected at Screening only.

A complete physical examination included, at a minimum, assessment ofthe cardiovascular, respiratory, gastrointestinal, and neurologicalsystems. Height and weight were also measured and recorded. At Screeningand Baseline/Randomization visits, BMI was calculated by the site inorder to verify eligibility.

Vital signs included oral temperature, pulse rate, respiratory rate, andBP. Clinically significant abnormal vital signs results reported duringScreening/Randomization were recorded as medical history and thosereported after study drug were recorded as AEs.

Blood pressure and pulse measurements were assessed with the subject ina seated or supine position and resting for at least 5 minutes prior totaking the measurement. The dominant arm was used for blood pressure andpulse rate measurements. On Day 1, vital signs were collected atpredose, and at approximately 2 (blood pressure and pulse) and 4 hours(blood pressure and pulse) postdose.

The 12-lead ECGs were collected at Screening, Day −1 until Day 4. Single12-lead ECG was obtained using an ECG machine that automaticallycalculated the heart rate and measured PR, QRS, QT, and corrected QTinterval (QTc) intervals. Any abnormal safety assessments including ECGreadings considered clinically significant in the medical and scientificjudgment of the investigator were reported as an AE. The investigatorhad to review the ECG and document it in the source documents.Clinically significant abnormal ECG results reported during Screeningwere recorded as medical history and those reported after study drugwere recorded as AEs.

All laboratory tests were to be performed in accordance with LaboratoryManual. The tests detailed in Table 7 were performed by the centrallaboratory. Additional tests might be performed at any time during thestudy as determined necessary by the investigator or required by localregulations.

All laboratory tests with abnormal values considered clinicallysignificant during the study or within 14 days after the last dose ofstudy drug (and considered by the investigator to be related to studydrug) were repeated until the values return to normal or Baseline orwere no longer considered clinically significant by the investigator ormedical monitor. If clinically significant values did not return tonormal/Baseline within a period of time judged reasonable by theinvestigator, the etiology were to be identified.

TABLE 7 Safety Laboratory Test Hematology: Serum Chemistry: Completeblood count (CBC), Albumin (ALB) including platelet count and Alkalinephosphatase (ALK-P) white blood cell count (WBC) with differentialAlanine aminotransferase (ALT) (absolute count and percent) Aspartateaminotransferase (AST) Urinalysis: Blood urea nitrogen (BUN) AppearanceCalcium (Ca) Bilirubin Carbon dioxide (CO2) Color Chloride (Cl) GlucoseCreatinine Ketones Creatine kinase Nitrite Glucose Occult bloodPhosphorus pH Potassium (K) Protein Sodium (Na) Specific gravity Totalbilirubin Urobilinogen Direct bilirubin Leukocyte esterase Totalcholesterol Total protein Triglycerides Uric acid Drug Screening:Pregnancy*: Urine Drug Screen Serum at Screening (amphetamines,barbiturates, Urine at Baseline (Day −1) benzodiazepines, cocaine,marijuana, opiates, phencyclidine) Breath alcohol test ALB = albumin;ALK-P = alkaline phosphatase; ALT = alanine aminotransferase; AST =aspartate aminotransferase; BUN = blood urea nitrogen; Ca = calcium; CBC= complete blood count; CO2—carbon dioxide; Cl = chlorine; K =potassium; Na = sodium; WBC = white blood cell count. *Pregnancyscreening required for all subjects in the study.Statistical/Analytical

Unless otherwise specified, continuous data was summarized usingdescriptive statistics comprising of the number of subjects exposed (N)and with data to be summarized (n), mean, standard deviation (SD),median, minimum (min), maximum (max), geometric mean (Geo-mean),coefficient of variation (CV %), and geometric coefficient of variation(CV %). Categorical variables were presented using counts andpercentages. Analyses and summary outputs were generated using SAS®Version 9.4 (SAS Institute, Inc., Cary, North Carolina, USA).

The PK Population consisted of all subjects who received study drug andprovided postdose breast milk or plasma PK data for at least onecollection interval or time point. This population was used forevaluable PK concentration data and PK parameter summaries and listings.The Safety Population consisted of all subjects who received the dose ofstudy drug. This population was used for demographic and baselinecharacteristics and for safety data summaries and listings.

Pharmacokinetic concentrations and parameters were summarized usingdescriptive statistics, including n, arithmetic mean, SD, coefficient ofvariation (CV %), median, min, max, Geometric mean (Geo-mean) and thegeometric coefficient of variation (Geo-CV %). For the PK parametert_(max), only n, median, minimum, and maximum was presented.

Subjects with partial data were evaluated on a case-by-case basis todetermine if sufficient data was available for reliable calculation ofPK parameters. In case of an incomplete milk collection (partial/spiltsample with inaccurate information of the total milk volume of theby-interval samples), the by-interval recovery was listed but notincluded in the summary, and cumulative recovery was only reportedthrough the most recent prior complete milk collection. By-interval dataduring which a subject was unable to lactate (produce any milk), wastreated as an amount of zero (for the affected interval) in thesummation of cumulative recovery calculation.

Plasma and milk concentrations were summarized using descriptivestatistics. Concentrations that were below the lower limit ofquantitation (BLQ) were treated as follows for the computation ofdescriptive statistics:

The summary statistics at a time with one or more BLQ values werecalculated by assigning ½ LLOQ to all values less than LLOQ. If thecalculated arithmetic (and geometric) mean value was BLQ, then SD and CV% were presented as “ND.”, and the mean was presented as “BLQ. However,since a high proportion of BLQ values may have affected the SD; if morethan 50% of values were imputed, then no mean was calculated for thattime point and again a value of BLQ was presented only for the meanvalue. Within the summary statistics, any minimum, or median values thatwere calculated to be BLQ were presented as BLQ within the summarypresentation.

Concentrations collected outside of the protocol allowed samplingwindows were included in descriptive statistics, unless the PK scientistobserved that the deviation was substantial enough to impact descriptivestatistics. In this case, the excluded concentrations were identified inthe CSR.

For plotting arithmetic mean concentration profiles: The arithmetic meanvalue at a time with one or more BLQ values were calculated by assigning½ LLOQ to all values BLQ. If the calculated mean value was BLQ, thenthat time point was plotted as zero in the mean pharmacokineticprofiles. However, since a high proportion of BLQ values may haveaffected the SD; if more than 50% of values were imputed, then no meanwas calculated for that time point and again a value of zero plotted. Aline with a label of LLOQ in the concentration axis was overlaid to showthe level of LLOQ.

Safety analyses were based on the Safety Population. The secondaryendpoints for evaluating subject safety and tolerance were the incidenceof reported AEs and the laboratory test results for all subjects.

Adverse events: Adverse events recorded in the electronic case reportforms (eCRFs) were coded to SOC and PT using the Medical Dictionary forRegulatory Activities (MedDRA). Treatment-emergent adverse events(TEAEs) are defined as any event with onset date on or after the firstdose of study drug or any ongoing event that worsened in severity afterthe date of the first dose of study drug or any event that was presentat baseline but was subsequently considered drug-related by theinvestigator through the end of the study. The incidence of TEAEs werepresented by severity, relationship to study drug, start and end date,seriousness, and outcome. The investigator assessed the severity andrelatedness of each AE to study drug. Columbia-Suicide Severity RatingScale (C-SSRS) data were summarized at scheduled visits and were listed.Other safety analyses were performed as appropriate.

12 Lead ECG: The number and percentage of subjects who had the followingpostbaseline clinically notable ECG interval abnormality was summarized:Ventricular rate ≥100 beats/min or ≤60 beats/min; PR interval ≥200 msecor ≤120 msec; QRS duration ≥100 msec or ≤80 msec; QT interval ≥440 msecor ≤350 msec; QTc Bazett and QTc Fredericia ≥470 msec or ≤330 msec; RRinterval ≥1200 msec or ≤600 msec; and QTc Bazette and QTc Fredericiaincrease from study Baseline Value ≥30 msec.

Vital Signs: The following clinically notable vital sign abnormalitieswere presented: Average systolic blood pressure ≥150 mmHg or ≤80 mmHg;Average diastolic blood pressure ≥mmHg or ≤60 mmHg; Average heart rate≥120 bpm or ≤50 bpm; Respiratory rate ≤10 breaths/min or ≥24breaths/min; Body temperature ≥37.9° C. or ≤35.5° C.; Systolic anddiastolic blood pressure change by ≥20% from the study baselinevalue/recordings; Pulse change by ≥20% from the study baselinevalue/recordings; Change in body weight by ≥7% from subject's baselinevalue (weight loss/weight gain); and Change in body temperature ≥1.8%from the subject's baseline temperature recordings.

Physical Examination: Physical examination data for each subject waspresented in a listing. A clinically significant adverse change (i.e.,worsening) of a physical examination finding after screening wasrecorded as an AE.

Disposition of Subjects. A total of 6 subjects were enrolled and treatedin the study. All 6 subjects had completed the study. There were nopremature discontinuations reported in the study. All 6 subjectsreceived the study drug (safety population) and provided post-dosebreast milk or plasma PK data for at least one collection interval ortime point (PK population). All 6 subjects were females and belonged tonot Hispanic or Latino ethnicity. The mean (SD) of age, weight, height,and BMI of the overall population was 28.7 (5.54) years, 79.15 (12.162)kg, 168.62 (6.013) cm, and 27.90 (4.513) kg/m², respectively.

TABLE 8 Demographics and Baseline Characteristics (Safety Population)Solriamfetol 150 mg Characteristic (N = 6) Age (years) n 6 Mean (SD)28.7 (5.54) Median 29.5 Min, Max 21,35 Gender, n (%) Female 6 (100%)Missing 0 Race, n (%) White 3 (50.0) Black or African American 3 (50.0)Missing 0 Ethnicity, n (%) Not Hispanic or Latino 6 (100%) Missing 0Height (cm) n 6 Mean (SD) 168.62 (6.013) Median 170.00 Min, Max 160.0,177.5 Weight (kg) n 6 Mean (SD) 79.15 (12.162) Median 77.90 Min, Max64.1, 99.1 BMI (kg/m²) n 6 Mean (SD) 27.90 (4.513) Median 27.95 Min, Max22.4, 34.3 BMI = body mass index; N = number of subjects exposed Note:Percentages are based on N.

Prior and Concomitant Medication: Two subjects had taken medicationsduring the study for AEs. One subject received acetaminophen and otherreceived ibuprofen.

Medical and Surgical History: A total of 5 of 6 subjects had the medicaland surgical history. Of these subjects, 1 subject had the medicalhistory of appendectomy, C-section, and tubal ligation. One subject hadasthma and C-section. One subject had cholelithiasis, pancreatitis, andgall bladder removal. One subject had umbilical hernia repair,heartburn, and C-section, and 1 subject had natural childbirth and hippain dur to natural childbirth.

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The foregoing is illustrative of the present invention and is not to beconstrued as limiting thereof. The invention is defined by the followingclaims, with equivalents of the claims to be included therein. Allpublications, patent applications, patents, patent publications, and anyother references cited herein are incorporated by reference in theirentireties for the teachings relevant to the sentence and/or paragraphin which the reference is presented.

What is claimed is:
 1. A method of preventing a reduction in number offeedings and/or a reduction in volume of milk ingested in an infant fedbreast milk obtained from a subject treated with solriamfetol,comprising orally administering the solriamfetol to the subject at adaily dose of about 150 mg; and feeding the infant breast milk obtainedfrom the subject at least about 5 hours after administering thesolriamfetol to the subject, wherein the daily infant dose ofsolriamfetol is about 0.3 mg or lower.
 2. The method of claim 1, whereinthe subject is from 1 day to 24 months postpartum.
 3. The method ofclaim 1, wherein the subject is from 10 days to 12 months postpartum. 4.The method of claim 1, wherein the subject is being treated withsolriamfetol for excessive daytime sleepiness, narcolepsy, obstructivesleep apnea, shift work disorder, attention deficit hyperactivitydisorder, depression, binge eating disorder, Parkinson's disease, orcognitive impairment.
 5. The method of claim 4, wherein the excessivedaytime sleepiness is associated with narcolepsy, obstructive sleepapnea, shift work, major depression, or Parkinson's disease.
 6. Themethod of claim 4, wherein the cognitive impairment is associated withnarcolepsy, obstructive sleep apnea, shift work, Parkinson's disease, orattention deficit hyperactivity disorder.
 7. The method of claim 1,wherein the subject is being treated with solriamfetol to improvewakefulness.
 8. The method of claim 1, wherein the subject is a womanbetween the ages of 18 and 50 years.
 9. A method of preventing areduction in number of feedings and/or a reduction in volume of milkingested in an infant fed breast milk obtained from a subject treatedwith solriamfetol, comprising orally administering the solriamfetol tothe subject at a daily dose of about 75 mg; and feeding the infantbreast milk obtained from the subject at least about 5 hours afteradministering the solriamfetol to the subject, wherein the daily infantdose of solriamfetol is about 0.15 mg or lower.
 10. The method of claim9, wherein the subject is from 1 day to 24 months postpartum.
 11. Themethod of claim 9, wherein the subject is from 10 44 days to 12 monthspostpartum.
 12. The method of claim 9, wherein the subject is beingtreated with solriamfetol for excessive daytime sleepiness, narcolepsy,obstructive sleep apnea, shift work disorder, attention deficithyperactivity disorder, depression, binge eating disorder, Parkinson'sdisease, or cognitive impairment.
 13. The method of claim 12, whereinthe excessive daytime sleepiness is associated with narcolepsy,obstructive sleep apnea, shift work, major depression, or Parkinson'sdisease.
 14. The method of claim 12, wherein the cognitive impairment isassociated with narcolepsy, obstructive sleep apnea, shift work,Parkinson's disease, or attention deficit hyperactivity disorder. 15.The method of claim 9, wherein the subject is being treated withsolriamfetol to improve wakefulness.
 16. The method of claim 9, whereinthe subject is a woman between the ages of 18 and 50 years.